Ionic silicone hydrogels having improved hydrolytic stability

ABSTRACT

The present invention relates to ionic silicone hydrogel polymers displaying improved thermal stability. More specifically, the present invention relates to a polymer formed from reactive components comprising at least one silicone component and at least one ionic component comprising at least one anionic group. The polymers of the present invention display good thermal stability and desirable protein uptake.

RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.13/898,919 filed May 21, 2013; which is a division of U.S. patentapplication Ser. No. 12/567,352 filed Sep. 25, 2009; which claimspriority to U.S. Provisional Patent Application Ser. No. 61/101,455filed on Sep. 30, 2008, the contents of which are relied upon andincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to ionic silicone hydrogels, andophthalmic devices formed therefrom, which display desirable proteinuptake profiles and improved hydrolytic stability.

BACKGROUND OF THE INVENTION

It is well known that contact lenses can be used to improve vision.Various contact lenses have been commercially produced for many years.Hydrogel contact lenses are very popular today. These lenses are formedfrom hydrophilic polymers and copolymers containing repeating units fromhydroxyethylmethylacrylate (HEMA). Of these contact lenses formed fromcopolymers of HEMA and methacrylic acid, are among the most comfortable,and have the lowest rate of adverse events. Contact lenses formed fromcopolymers of HEMA and MAA, such ACUVUE contact lenses, displaysubstantial amounts of lysozyme uptake (greater than 500 μg) and retaina majority of the uptaken proteins in their native state. However,hydrogel contact lenses generally have oxygen permeabilities that areless than about 30.

Contact lenses made from silicone hydrogels have been disclosed. Thesesilicone hydrogel lenses have oxygen permeabilities greater than about60, and many provide reduced levels of hypoxia compared to conventionalhydrogel contact lenses. However, silicone hydrogel lenses havedifferent rates for adverse events than conventional hydrogels, and itwould be desirable to maintain the oxygen transmissibility of a siliconehydrogel, but achieve the low adverse event rate of the bestconventional hydrogel lenses. Unfortunately, attempts to add anioniccomponents to silicone hydrogels in the past have produced contactlenses which are not hydrolytically stable and display moduli whichincrease when exposed to water and heat. For example, the modulus ofPurevision lenses (Bausch & Lomb) increase from 155 psi to 576 psi whenheated at 95° C. for one week. It is believed that the cause of thisincrease in modulus is the hydrolysis of terminal siloxane groupsfollowed by condensation reactions to form new siloxane bonds andintroduce new crosslinks. Even though Purevision lenses contain about 1weight % ionicity, they uptake relatively low lysozyme levels (less thanabout 50 μg), and a majority of the protein uptaken is denatured.

It has been suggested that the instability of ionic silicone hydrogelscould be reduced by using silicones components having bulky alkyl oraryl groups instead of silicone monomers such as3-methacryloxypropyltris(trimethylsiloxy)silane (“TRIS”) or2-methyl-,2-hydroxy-3-[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propoxy]propylester (“SiGMA”). However, the bulky siloxane monomers are notcommercially available and may be expensive to make.

SUMMARY OF THE INVENTION

The present invention relates to ionic silicone hydrogel polymersdisplaying improved thermal stability and desirable protein uptake. Morespecifically, the present invention relates to silicone hydrogelpolymers and contact lenses formed from reactive components comprisingat least one silicone component and at least one anionic component in anamount between about 0.1 and 0.8 wt %.

The present invention relates to ionic silicone hydrogel polymersdisplaying improved thermal stability and desirable protein uptake. Morespecifically, the present invention relates to silicone hydrogel polymerand contact lenses formed from reactive components comprising at leastone silicone component and at least one anionic component comprising atleast one carboxylic acid group in an amount between about 0.1 and about10 mmol/gm.

DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the change in modulus at 55° C. of the lensesof Examples 1-4 and Comparative Example 1 as a function of time.

FIGS. 2-4 are graphs showing, for the lenses of Examples 6-7, the changein modulus, toughness and elongation at 55° C. as a function of time.

FIG. 5 is graph showing the concentrations of PQ-1 and lysozyme uptakenin the polymer formed in Examples 10-18 and Comparative Example 2.

DETAILED DESCRIPTION

It has been surprisingly found that ionic silicone hydrogel polymers andarticles made therefrom may be made having acceptable thermal stabilityand desirable protein uptake characteristics.

As used herein, a “biomedical device” is any article that is designed tobe used while either in or on mammalian tissues or fluid. Examples ofthese devices include but are not limited to catheters, implants,stents, and ophthalmic devices such as intraocular lenses and contactlenses.

As used herein an “ophthalmic device” is any device which resides in oron the eye or any part of the eye, including the cornea, eyelids andocular glands. These devices can provide optical correction, cosmeticenhancement, vision enhancement, therapeutic benefit (for example asbandages) or delivery of active components such as pharmaceutical andneutraceutical components, or a combination of any of the foregoing.Examples of ophthalmic devices include lenses and optical and ocularinserts, including, but not limited to punctal plugs and the like.

As used herein, the term “lens” refers to ophthalmic devices that residein or on the eye. The term lens includes but is not limited to softcontact lenses, hard contact lenses, intraocular lenses, overlay lenses.

The medical devices, ophthalmic devices and lenses of the presentinvention are made from silicone elastomers or hydrogels, which includebut are not limited to silicone hydrogels, and silicone-fluorohydrogels.These hydrogels contain hydrophobic and hydrophilic monomers that arecovalently bound to one another in the cured lens. As used herein“uptake” means associated in, with or on the lens, deposited in or onthe lens.

As used herein “reactive mixture” refers to the mixture of components(both reactive and non-reactive) which are mixed together and subjectedto polymerization conditions to form the ionic silicone hydrogels of thepresent invention. The reactive mixture comprises reactive componentssuch as monomers, macromers, prepolymers; cross-linkers, initiators,diluents and additives such as wetting agents, release agents, dyes,light absorbing compounds such as UV absorbers and photochromiccompounds, any of which may be reactive or non-reactive but are capableof being retained within the resulting medical device, as well aspharmaceutical and neutriceutical compounds. It will be appreciated thata wide range of additives may be added based upon the medical devicewhich is made, and its intended use. Concentrations of components of thereactive mixture are given in weight % of all components in the reactionmixture, excluding diluent. When diluents are used their concentrationsare given as weight % based upon the amount of all components in thereaction mixture and the diluent.

Anionic components are components comprising at least one anionic groupand at least one reactive group. Anionic groups are groups which bear anegative charge. Examples of anionic groups include carboxylate groups,phosphates, sulfates, sulfonates, phosphonates, borates, mixturesthereof and the like. In one embodiment the anionic groups comprisethree to ten carbon atoms, and in another, three to eight carbon atoms.In an embodiment the anionic groups comprise carboxylic acid groups.

Reactive groups include groups that can undergo free radical and/orcationic polymerization under polymerization conditions. Non-limitingexamples of free radical reactive groups include (meth)acrylates,styryls, vinyls, vinyl ethers, C₁₋₆alkyl(meth)acrylates,(meth)acrylamides, C₁₋₆alkyl(meth)acrylamides, N-vinyllactams,N-vinylamides, C₂₋₁₂alkenyls, C₂₋₁₂alkenylphenyls,C₂₋₁₂alkenylnaphthyls, C₂₋₆alkenylphenylC₁₋₆alkyls, O-vinylcarbamatesand O-vinylcarbonates. Non-limiting examples of cationic reactive groupsinclude vinyl ethers or epoxide groups and mixtures thereof. In oneembodiment the reactive groups comprises (meth)acrylate, acryloxy,(meth)acrylamide, and mixtures thereof.

Any chemical name preceded by (meth), for example (meth)acrylate,includes both the unsubstituted and methyl substituted compound.

Examples of suitable anionic components include reactive carboxylicacids, including alkylacryl acids, such as (meth)acrylic acid, acrylicacid, itaconic acid, crotonic acid, cinnamic acid, vinylbenzoic acid,fumaric acid, maleic acid, monoesters of furmaric acid, maelic acid anditaconic acid; N-vinyloxycarbonyl alanine (VINAL), reactive sulfonatesalts, including sodium-2-(acrylamido)-2-methylpropane sulphonate,3-sulphopropyl (meth)acrylate potassium salt, 3-sulphopropyl(meth)acrylate sodium salt, bis 3-sulphopropyl itaconate di sodium, bis3-sulphopropyl itaconate di potassium, vinyl sulphonate sodium salt,vinyl sulphonate salt, styrene sulfonate, sulfoethyl methacrylate andmixtures thereof and the like. In one embodiment the anionic componentis selected from reactive carboxylic acids, in another from methacrylicacid and N-vinyloxycarbonyl alanine. In one embodiment the ioniccomponent comprises methacrylic acid.

In one embodiment, the anionic components is included in the reactivemixture in amounts between about 0.05 and about 0.8 weight % and in someembodiments between about 0.1 and about 0.8 weight %.

In another embodiment, the anionic component comprises at least onecarboxylic acid group and is present in the reactive mixture in amountsbetween about 0.1 mmol/100 g and about 10 mmol/g. By maintaining theconcentration of anioinic component within the ranges recited herein,the stability of the polymer may be improved. Surprisingly, it has beenfound that polymers having the amounts of anionic component recitedherein have desirable protein uptake profiles in addition to improvedstability.

In another embodiment, the amount of anionic component may vary basedupon the structure and concentration of the silicone components as wellas the structure of the anionic component so long as the molar productof the anionic groups and the Si from TMS groups is below the moleproduct described below.

The silicone hydrogel polymers of the present invention display stablemodulus. As used herein, stable modulus are those which increase lessthan about 30%, and in some embodiments less than about 20% over eightweeks, at 55° C. In some embodiments the silicone hydrogel polymers ofthe present invention display modulus that increase by less than about20% over 20 weeks at 55° C.

Silicone components are reactive and non-reactive components whichcomprise at least one “—Si—O—Si—” group. It is preferred that siliconeand its attached oxygen account for about 10 weight percent of saidsilicone component, more preferably more than about 20 weight percent.

Prior attempts to add anionic components to silicone hydrogels havegenerally resulted in polymers which display modulii which increase overtime or when exposed to heat. It is believed that the cause of theincreasing modulus is the hydrolysis of terminal siloxane groupsfollowed by condensation reactions to form new siloxane bonds andintroduce new crosslinks. Hydrolytic stability of silicone groups(specifically the silicon-oxygen bond) is believed to be influenced bythe substituents on the Si atom. Bulkier groups provide greaterhydrolytic stability through increased steric hindrance. Thesubstituents can be alkyl groups (methyl, ethyl, propyl, butyl etc.),aryl (e.g. benzyl) or even other silicon-containing groups. On the basisof steric hindrance, silicone materials containing trimethylsilyl(—OSiMe₃) groups (such as SiMAA or TRIS) are generally lesshydrolytically stable in the presence of ionic components than compoundscontaining polydimethylsiloxane [(—OSiMe₂)] chains, such as mPDMS. Thus,in this embodiment, the stability of the polymer is further improved byselection of the silicone containing components in combination withcontrolling the concentration of the anionic component.

In one embodiment, the silicone component comprises at least onepolydimethylsiloxane chain, and in another embodiment, all siliconecomponents are free of TMS groups.

In one embodiment of the present invention the product of the molepercent of silicon (Si) in a trimethylsilyl (TMS) group in the siliconecomponent and mole % anionic group in the ionic component is less thanabout 0.002, in some embodiments less than about 0.001 and in othersless than about 0.0006. This is calculated as follows:

1) In calculating the mole fractions according to the present invention,the reactive components of the monomer mix (i.e. excluding diluent(s)and processing aids which are not permanently incorporated into thelens) are represented as weight fractions summing up to a total of 100g.

2) The moles anionic group=(grams of anionic component/MW of anioniccomponent)*number of anionic groups in the anionic component. ForExample 1, containing 1% methacylic acid, the calculation is (1 gm/86gm/mol)*1=0.012 moles carboxylate.

3) The moles TMS=(grams silicone component/MW of siliconecomponent)*number of TMS groups per silicone component. For example, inExample 1, containing 30 gm SiMAA the calculation is (30 gm/422.7gm/mol)*2=0.142 moles TMS. In formulations containing a plurality ofsilicone components having TMS groups, the moles TMS are calculated foreach silicone component and then summed.

4) The stability product is calculated by multiplying the values for themoles carboxylate and mole TMS. Thus the stability product for Example 1is 0.012*0.142=0.0017.

Thus, in this embodiment, the silicone components, ionic components andtheir amounts used to make hydrogels of the present invention areselected such that the stability product, does not exceed the valuesspecified herein. In another embodiment, the silicone components usedcontain no TMS groups, thereby providing stability products of zero.Silicone-containing components which contain no TMS groups include thosedisclosed in WO2008/042158, and reactive PDMS components of Formula I:

wherein b is 2 to 20, 3 to 15 or in some embodiments 3 to 10; at leastone terminal R¹ comprises a monovalent reactive group, the otherterminal R¹ comprises a monovalent reactive group or a monovalent alkylgroup having 1 to 16 carbon atoms, and the remaining R¹ are selectedfrom monovalent alkyl groups having 1 to 16 carbon atoms, and in anotherembodiment from monovalent alkyl groups having 1 to 6 carbon atoms. Inyet another embodiment, b is 3 to 15, one terminal R¹ comprises amonovalent reactive group, for example, a (meth)acryloxy C₁₋₆ alkyl,which may be further substituted with at least one hydrophilic group,such as hydroxyl, ether or a combination thereof, the other terminal R¹comprises a monovalent alkyl group having 1 to 6 carbon atoms and theremaining R¹ comprise monovalent alkyl group having 1 to 3 carbon atoms.In one embodiment one terminal R¹ is (meth)acryloxy C₁₋₆ alkyl, which isoptionally substituted with ether or hydroxyl, the other terminal R¹ isa C₁₋₄ alkyl, and the remaining R¹ are methyl or ethyl. Non-limitingexamples of PDMS components of this embodiment include(mono-(2-hydroxy-3-methacryloxypropyl)-propyl ether terminatedpolydimethylsiloxane (400-1000 MW)) (“HO-mPDMS”), andmonomethacryloxypropyl terminated mono-n-C₁₋₄ alkyl terminatedpolydimethylsiloxanes, including monomethacryloxypropyl terminatedmono-n-butyl terminated polydimethylsiloxanes (800-1000 MW), (“mPDMS”)and monomethacryloxypropyl terminated methyl terminatedpolydimethylsiloxanes (800-1000 MW), (“mPDMS”). In one embodiment allsilicone in the reactive mixture are PDMS components.

In another embodiment b is 5 to 400 or from 10 to 300, both terminal R¹comprise monovalent reactive groups and the remaining R¹ areindependently selected from monovalent alkyl groups having 1 to 18carbon atoms which may have ether linkages between carbon atoms and mayfurther comprise halogen.

In another embodiment, one to four R¹ comprises a vinyl carbonate orcarbamate of the formula:

wherein: Y denotes O—, S— or NH—;R denotes, hydrogen or methyl; q is 1, 2, 3 or 4; and b is 1-50. Inthese embodiments care must be taken to make sure the vinyl carbonate orcarbamate silicone component does not also comprising TMS groups, or themole product ratios specified herein will be difficult to achieve.

Suitable silicone-containing vinyl carbonate or vinyl carbamate monomersspecifically include:1,3-bis[4-(vinyloxycarbonyloxy)but-1-yl]tetramethyl-disiloxane; and

wherein R¹ is as defined for a terminal group above.

In some embodiments, small amounts of vinyl carbamate and vinylcarbonate compounds comprising TMS groups may be used. Such groupsinclude 3-(vinyloxycarbonylthio) propyl-[tris (trimethylsiloxy)silane];3-[tris(trimethylsiloxy)silyl] propyl allyl carbamate;3-[tris(trimethylsiloxy)silyl] propyl vinyl carbamate;trimethylsilylethyl vinyl carbonate; trimethylsilylmethyl vinylcarbonate, combinations thereof and the like.

In some embodiments it may be desirable to add small amounts ofsilicone-containing components which comprise at least one TMS group.Such groups include the TMS containing vinyl carbonate and carbamatesdescribed above, as well as silicone-containing components of Formula Iwhere R¹ is independently selected from monovalent reactive groups,monovalent alkyl groups, or monovalent aryl groups, any of the foregoingwhich may further comprise functionality selected from hydroxy, amino,oxa, carboxy, alkyl carboxy, alkoxy, amido, carbamate, carbonate,halogen or combinations thereof; and monovalent trimethyl siloxanegroups;

where b=0;

wherein at least one R¹ comprises a monovalent reactive group, and insome embodiments between one and 3 R¹ comprise monovalent reactivegroups.

Suitable monovalent alkyl and aryl groups include unsubstitutedmonovalent C₁ to C₁₆alkyl groups, C₆-C₁₄ aryl groups, such assubstituted and unsubstituted methyl, ethyl, propyl, butyl,2-hydroxypropyl, propoxypropyl, polyethyleneoxypropyl, combinationsthereof and the like.

In one embodiment b is zero, one R¹ is a monovalent reactive group, andat least 3 R¹ are selected from monovalent alkyl groups having one to 16carbon atoms, and in another embodiment from monovalent alkyl groupshaving one to 6 carbon atoms.

Non-limiting examples of silicone components of this embodiment include2-methyl-,2-hydroxy-3-[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propoxy]propyl ester (“SiGMA”),2-hydroxy-3-methacryloxypropyloxypropyl-tris(trimethylsiloxy)silane,3-methacryloxypropyltris(trimethylsiloxy)silane (“TRIS”),3-methacryloxypropylbis(trimethylsiloxy)methylsilane and3-methacryloxypropylpentamethyl disiloxane.

When included, silicone containing components comprising TMS groups arepresent in amounts less than about 20 weight %, less than about 10 wt %,and in some embodiments, less than about 5 wt %.

Where biomedical devices with modulus below about 200 are desired, onlyone R¹ shall comprise a monovalent reactive group.

In one embodiment, where a silicone hydrogel lens is desired, the lensof the present invention will be made from a reactive mixture comprisingat least about 20 weight % and in some embodiments between about 20 and70% wt silicone-containing components based on total weight of reactivemonomer components from which the polymer is made.

Another class of silicone-containing components includes polyurethanemacromers of the following formulae:(*D*A*D*G)_(a)*D*D*E¹;E(*D*G*D*A)_(a)*D*G*D*E¹ or;E(*D*A*D*G)_(a)*D*A*D*E¹  Formulae IV-VIwherein:D denotes an alkyl diradical, an alkyl cycloalkyl diradical, acycloalkyl diradical, an aryl diradical or an alkylaryl diradical having6 to 30 carbon atoms,G denotes an alkyl diradical, a cycloalkyl diradical, an alkylcycloalkyl diradical, an aryl diradical or an alkylaryl diradical having1 to 40 carbon atoms and which may contain ether, thio or amine linkagesin the main chain;* denotes a urethane or ureido linkage;_(a) is at least 1;A denotes a divalent polymeric radical of formula:

R¹¹ independently denotes an alkyl or fluoro-substituted alkyl grouphaving 1 to10 carbon atoms which may contain ether linkages betweencarbon atoms; y is at least 1; and p provides a moiety weight of 400 to10,000; each of E and E¹ independently denotes a polymerizableunsaturated organic radical represented by formula:

wherein: R¹² is hydrogen or methyl; R¹³ is hydrogen, an alkyl radicalhaving 1 to 6 carbon atoms, or a —CO—Y—R¹⁵ radical wherein Y is —O—,Y—S—or —NH—; R¹⁴ is a divalent radical having 1 to 12 carbon atoms; Xdenotes —CO— or —OCO—; Z denotes —O— or —NH—; Ar denotes an aromaticradical having 6 to 30 carbon atoms; w is 0 to 6; x is 0 or 1; y is 0 or1; and z is 0 or 1.

In one embodiment the silicone-containing component comprises apolyurethane macromer represented by the following formula:

wherein R¹⁶ is a diradical of a diisocyanate after removal of theisocyanate group, such as the diradical of isophorone diisocyanate.Another suitable silicone containing macromer is compound of formula X(in which x+y is a number in the range of 10 to 30) formed by thereaction of fluoroether, hydroxy-terminated polydimethylsiloxane,isophorone diisocyanate and isocyanatoethylmethacrylate.

Other silicone-containing components suitable for use in this inventioninclude those described is WO 96/31792 such as macromers containingpolysiloxane, polyalkylene ether, diisocyanate, polyfluorinatedhydrocarbon, polyfluorinated ether and polysaccharide groups. Anotherclass of suitable silicone-containing components include siliconecontaining macromers made via GTP, such as those disclosed in U.S. Pat.Nos. 5,314,960, 5,331,067, 5,244,981, 5,371,147 and 6,367,929. U.S. Pat.Nos. 5,321,108; 5,387,662 and 5,539,016 describe polysiloxanes with apolar fluorinated graft or side group having a hydrogen atom attached toa terminal difluoro-substituted carbon atom. US 2002/0016383 describehydrophilic siloxanyl methacrylates containing ether and siloxanyllinkanges and crosslinkable monomers containing polyether andpolysiloxanyl groups. Any of the foregoing polysiloxanes can also beused as the silicone-containing component in this invention.

In one embodiment of the present invention where a modulus of less thanabout 120 psi is desired, the majority of the mass fraction of thesilicone-containing components used in the lens formulation shouldcontain only one polymerizable functional group (“monofunctionalsilicone containing component”). In this embodiment, to insure thedesired balance of oxygen transmissibility and modulus it is preferredthat all components having more than one polymerizable functional group(“multifunctional components”) make up no more than 10 mmol/100 g of thereactive components, and preferably no more than 7 mmol/100 g of thereactive components.

The silicone containing components may be present in amounts up to about95 weight %, and in some embodiments between about 10 and about 80 andin other embodiments between about 20 and about 70 weight %, based uponall reactive components.

The reactive mixture may also comprise at least one hydrophiliccomponent in addition to the ionic component. Hydrophilic monomers canbe any of the hydrophilic monomers known to be useful to make hydrogels.

One class of suitable hydrophilic monomers include acrylic- orvinyl-containing monomers. Such hydrophilic monomers may themselves beused as crosslinking agents, however, where hydrophilic monomers havingmore than one polymerizable functional group are used, theirconcentration should be limited as discussed above to provide a contactlens having the desired modulus. The term “vinyl-type” or“vinyl-containing” monomers refer to monomers containing the vinylgrouping (—CH═CH₂) and are generally highly reactive. Such hydrophilicvinyl-containing monomers are known to polymerize relatively easily.

“Acrylic-type” or “acrylic-containing” monomers are those monomerscontaining the acrylic group: (CH₂═CRCOX) wherein R is H or CH₃, and Xis O or N, which are also known to polymerize readily, such asN,N-dimethyl acrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA),glycerol methacrylate, 2-hydroxyethyl methacrylamide, polyethyleneglycolmonomethacrylate, mixtures thereof and the like.

Hydrophilic vinyl-containing monomers which may be incorporated into thesilicone hydrogels of the present invention include monomers such asN-vinyl amides, N-vinyl lactams (e.g. NVP), N-vinyl-N-methyl acetamide,N-vinyl-N-ethyl acetamide, N-vinyl-N-ethyl formamide, N-vinyl formamide,with NVP being preferred.

Other hydrophilic monomers that can be employed in the invention includepolyoxyethylene polyols having one or more of the terminal hydroxylgroups replaced with a functional group containing a polymerizabledouble bond. Examples include polyethylene glycol, ethoxylated alkylglucoside, and ethoxylated bisphenol A reacted with one or more molarequivalents of an end-capping group such as isocyanatoethyl methacrylate(“IEM”), methacrylic anhydride, methacryloyl chloride, vinylbenzoylchloride, or the like, to produce a polyethylene polyol having one ormore terminal polymerizable olefinic groups bonded to the polyethylenepolyol through linking moieties such as carbamate or ester groups.

Still further examples are the hydrophilic vinyl carbonate or vinylcarbamate monomers disclosed in U.S. Pat. No. 5,070,215, and thehydrophilic oxazolone monomers disclosed in U.S. Pat. No. 4,910,277.Other suitable hydrophilic monomers will be apparent to one skilled inthe art.

In one embodiment the hydrophilic comprises at least one hydrophilicmonomer such as DMA, HEMA, glycerol methacrylate, 2-hydroxyethylmethacrylamide, NVP, N-vinyl-N-methyl acrylamide, polyethyleneglycolmonomethacrylate, and combinations thereof. In another embodiment, thehydrophilic monomers comprise at least one of DMA, HEMA, NVP andN-vinyl-N-methyl acrylamide and mixtures thereof. In another embodiment,the hydrophilic monomer comprises DMA.

The hydrophilic monomers may be present in a wide range of amounts,depending upon the specific balance of properties desired. Amounts ofhydrophilic monomer up to about 50 and preferably between about 5 andabout 50 weight %, based upon all reactive components are acceptable.For example, in one embodiment lenses of the present invention comprisea water content of at least about 25%, and in another embodiment betweenabout 30 and about 70%. For these embodiments, the hydrophilic monomermay be included in amounts between about 20 and about 50 weight %.

Other components that can be present in the reaction mixture used toform the contact lenses of this invention include wetting agents, suchas those disclosed in U.S. Pat. No. 6,367,929, WO03/22321, WO03/22322,compatibilizing components, such as those disclosed in US2003/162862 andUS2003/125498, ultra-violet absorbing compounds, medicinal agents,antimicrobial compounds, copolymerizable and nonpolymerizable dyes,release agents, reactive tints, pigments, combinations thereof and thelike. The sum of additional components may be up to about 20 wt %. Inone embodiment the reaction mixtures comprise up to about 18 wt %wetting agent, and in another embodiment, between about 5 and about 18wt % wetting agent.

A polymerization catalyst may be included in the reaction mixture. Thepolymerization initiators includes compounds such as lauryl peroxide,benzoyl peroxide, isopropyl percarbonate, azobisisobutyronitrile, andthe like, that generate free radicals at moderately elevatedtemperatures, and photoinitiator systems such as aromatic alpha-hydroxyketones, alkoxyoxybenzoins, acetophenones, acylphosphine oxides,bisacylphosphine oxides, and a tertiary amine plus a diketone, mixturesthereof and the like. Illustrative examples of photoinitiators are1-hydroxycyclohexyl phenyl ketone,2-hydroxy-2-methyl-1-phenyl-propan-1-one,bis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentyl phosphine oxide(DMBAPO), bis(2,4,6-trimethylbenzoyl)-phenyl phosphineoxide (Irgacure819), 2,4,6-trimethylbenzyldiphenyl phosphine oxide and2,4,6-trimethylbenzoyl diphenylphosphine oxide, benzoin methyl ester anda combination of camphorquinone and ethyl 4-(N,N-dimethylamino)benzoate.Commercially available visible light initiator systems include Irgacure819, Irgacure 1700, Irgacure 1800, Irgacure 819, Irgacure 1850 (all fromCiba Specialty Chemicals) and Lucirin TPO initiator (available fromBASF). Commercially available UV photoinitiators include Darocur 1173and Darocur 2959 (Ciba Specialty Chemicals). These and otherphotoinitators which may be used are disclosed in Volume III,Photoinitiators for Free Radical Cationic & Anionic Photopolymerization,2^(nd) Edition by J. V. Crivello & K. Dietliker; edited by G. Bradley;John Wiley and Sons; New York; 1998. The initiator is used in thereaction mixture in effective amounts to initiate photopolymerization ofthe reaction mixture, e.g., from about 0.1 to about 2 parts by weightper 100 parts of reactive monomer. Polymerization of the reactionmixture can be initiated using the appropriate choice of heat or visibleor ultraviolet light or other means depending on the polymerizationinitiator used. Alternatively, initiation can be conducted without aphotoinitiator using, for example, e-beam. However, when aphotoinitiator is used, the preferred initiators are bisacylphosphineoxides, such as bis(2,4,6-trimethylbenzoyl)-phenyl phosphine oxide(Irgacure 819®) or a combination of 1-hydroxycyclohexyl phenyl ketoneand bis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentyl phosphine oxide(DMBAPO), and in another embodiment the method of polymerizationinitiation is via visible light activation. A preferred initiator isbis(2,4,6-trimethylbenzoyl)-phenyl phosphine oxide (Irgacure 819®).

The reactive components (silicone containing component, hydrophilicmonomers, wetting agents, and other components which are reacted to formthe lens) are mixed together either with or without a diluent to formthe reaction mixture.

In one embodiment a diluent is used having a polarity sufficiently lowto solubilize the non-polar components in the reactive mixture atreaction conditions. One way to characterize the polarity of thediluents of the present invention is via the Hansen solubilityparameter, δp. In certain embodiments, the δp is less than about 10, andpreferably less than about 6. Suitable diluents are further disclosed inU.S. Ser. No. 60/452898 and U.S. Pat. No. 6,020,445.

Classes of suitable diluents include, without limitation, alcoholshaving 2 to 20 carbons, amides having 10 to 20 carbon atoms derived fromprimary amines, ethers, polyethers, ketones having 3 to 10 carbon atoms,and carboxylic acids having 8 to 20 carbon atoms. For all solvents, asthe number of carbons increase, the number of polar moieties may also beincreased to provide the desired level of water miscibility. In someembodiments, primary and tertiary alcohols are preferred. Preferredclasses include alcohols having 4 to 20 carbons and carboxylic acidshaving 10 to 20 carbon atoms.

In one embodiment the diluents are selected from 1,2-octanediol, t-amylalcohol, 3-methyl-3-pentanol, decanoic acid, 3,7-dimethyl-3-octanol,tripropylene methyl ether (TPME), butoxy ethyl acetate, mixtures thereofand the like.

In one embodiment the diluents are selected from diluents that have somedegree of solubility in water. In some embodiments at least about threepercent of the diluent is miscible water. Examples of water solublediluents include 1-octanol, 1-pentanol, 1-hexanol, 2-hexanol, 2-octanol,3-methyl-3-pentanol, 2-pentanol, t-amyl alcohol, tert-butanol,2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-ethyl-1-butanol, ethanol,3,3-dimethyl-2-butanol, decanoic acid, octanoic acid, dodecanoic acid,1-ethoxy-2-propanol, 1-tert-butoxy-2-propanol, EH-5 (commerciallyavailable from Ethox Chemicals),2,3,6,7-tetrahydroxy-2,3,6,7-tetramethyl octane,9-(1-methylethyl)-2,5,8,10,13,16-hexaoxaheptadecane,3,5,7,9,11,13-hexamethoxy-1-tetradecanol, mixtures thereof and the like.

The reactive mixture of the present invention may be cured via any knownprocess for molding the reaction mixture in the production of contactlenses, including spincasting and static casting. Spincasting methodsare disclosed in U.S. Pat. Nos. 3,408,429 and 3,660,545, and staticcasting methods are disclosed in U.S. Pat. Nos. 4,113,224 and 4,197,266.In one embodiment, the contact lenses of this invention are formed bythe direct molding of the silicone hydrogels, which is economical, andenables precise control over the final shape of the hydrated lens. Forthis method, the reaction mixture is placed in a mold having the shapeof the final desired silicone hydrogel, i.e. water-swollen polymer, andthe reaction mixture is subjected to conditions whereby the monomerspolymerize, to thereby produce a polymer in the approximate shape of thefinal desired product.

After curing the lens is subjected to extraction to remove unreactedcomponents and release the lens from the lens mold. The extraction maybe done using conventional extraction fluids, such organic solvents,such as alcohols or may be extracted using aqueous solutions.

Aqueous solutions are solutions which comprise water. In one embodimentthe aqueous solutions of the present invention comprise at least about30% water, in some embodiments at least about 50% water, in someembodiments at least about 70% water and in others at least about 90weight % water. Aqueous solutions may also include additional watersoluble components such as release agents, wetting agents, slip agents,pharmaceutical and nutraceutical components, combinations thereof andthe like. Release agents are compounds or mixtures of compounds which,when combined with water, decrease the time required to release acontact lens from a mold, as compared to the time required to releasesuch a lens using an aqueous solution that does not comprise the releaseagent. In one embodiment the aqueous solutions comprise less than about10 weight %, and in others less than about 5 weight % organic solventssuch as isopropyl alcohol, and in another embodiment are free fromorganic solvents. In these embodiments the aqueous solutions do notrequire special handling, such as purification, recycling or specialdisposal procedures.

In various embodiments, extraction can be accomplished, for example, viaimmersion of the lens in an aqueous solution or exposing the lens to aflow of an aqueous solution. In various embodiments, extraction can alsoinclude, for example, one or more of: heating the aqueous solution;stirring the aqueous solution; increasing the level of release aid inthe aqueous solution to a level sufficient to cause release of the lens;mechanical or ultrasonic agitation of the lens; and incorporating atleast one leach aid in the aqueous solution to a level sufficient tofacilitate adequate removal of unreacted components from the lens. Theforegoing may be conducted in batch or continuous processes, with orwithout the addition of heat, agitation or both.

Some embodiments can also include the application of physical agitationto facilitate leach and release. For example, the lens mold part towhich a lens is adhered, can be vibrated or caused to move back andforth within an aqueous solution. Other embodiments may includeultrasonic waves through the aqueous solution.

These and other similar processes can provide an acceptable means ofreleasing the lens.

As used herein, “released from a mold” means that a lens is eithercompletely separated from the mold, or is only loosely attached so thatit can be removed with mild agitation or pushed off with a swab. In theprocess of the present invention the conditions used include temperatureless than 99° C. for less than about 1 hour.

The lenses may be sterilized by known means such as, but not limited toautoclaving.

In addition to displaying desirable stability, the lenses of the presentinvention also display compatibility with the components of human tears.

Human tears are complex and contain a mixture of proteins, lipids andother components which help to keep the eye lubricated. Examples oflipids classes include wax ester, cholesterolesters and cholesterol.Examples of proteins which are found in human tears include lactoferrin,lysozyme, lipocalin, serum albumin, secretory immunoglobulin A.Lipocalin is a lipid binding protein. The amount of lipocalin uptake toa contact lens has been negatively correlated to lens wettability (asmeasured via contact angle, such as via sessile drop), the propensity oflenses to uptake lipids from the tear film and consequently deposits onthe front surface of the lens. Lenses which uptake low levels oflipocalin are therefore desirable. In one embodiment of the presentinvention, the lenses uptake less than about 3 μg lipocalin from a 2mg/ml lipocalin solution over 72 hours incubation at 35° C.

Lysozyme is generally present in human tears in substantialconcentrations. Lysozyme is bacteriolytic and believed to protect theeye against bacterial infection. The amount of lysozyme which associateswith commercially available contact lenses varies greatly from only afew micrograms to over 800 micrograms for etafilcon A contact lenses(commercially available from Johnson & Johnson Vision Care, Inc., underthe ACUVUE and ACUVUE2 brand names). Etafilcon A contact lenses havebeen commercially available for many years and display some of thelowest adverse event rates of any soft contact lens. Thus, contactlenses which uptake substantial levels of lysozyme are desirable. Thelenses of the present invention uptake at least about 50 μg, 100 μg, 200μg, 500 μg of lysozyme and in some embodiments at least about 800 μglysozyme, all from a 2 mg/ml solution over 72 hours incubation at 35° C.

In addition to lysozyme, lactoferrin is another important cationicprotein in the tears, mainly by the virtue of its anti-bacterial andanti-inflammatory properties. Upon wear, contact lenses uptake variousamounts of lactoferrin, depending upon their polymer composition (fornon-surface modified lenses) and the composition and integrity of thesurface coating (for surface modified contact lenses). In one embodimentof the present invention, lenses uptake at least about 5 μg, and in someembodiments, at least about 10 micrograms lactoferrin followingovernight soaking of the lenses in 2 mls of a 2 mg/ml lactoferrinsolution. The lactoferrin solution contains lactoferrin from human milk(Sigma L-0520) solubilized at a concentration of 2 mg/ml in phosphatesaline buffer. Lenses are incubated in 2 ml of the lactoferrin solutionper lens for 72 hours at 35° C., using the procedure described below forlipocalin and lysozyme.

The form of the proteins in, on and associated with the lens is alsoimportant. Denatured proteins are believed to contribute to cornealinflammatory events and wearer discomfort. Environmental factors such aspH, ocular surface temperature, wear time and closed eye wear arebelieved to contribute to the denaturation of proteins. However, lensesof different compositions can display markedly different protein uptakeand denaturation profiles. In one embodiment of the present invention, amajority of the proteins uptaken by the lenses of the present inventionare and remain in the native form during wear. In other embodiments atleast about 50%, at least about 70 and at least about 80% of uptakenproteins are and remain native after 24 hours, 3 days and during theintended wear period.

In one embodiment the ophthalmic devices of the present invention alsouptake less than about 20%, in some embodiments less than about 10%, andin other embodiments less than about 5% Polyquaternium-1(dimethyl-bis[(E)-4-[tris(2-hydroxyethyl)azaniumyl] but-2-enyl]azaniumtrichloride) (“PQ1”) from an ophthalmic solution containing 0.001 wt %PQ1).

The lenses of the present invention have a number of desirableproperties in addition to the protein uptake characteristics describedherein. In one embodiment the lenses have an oxygen permeability greaterthan about 50 and in other embodiment greater than about 60, in otherembodiments greater than about 80 and in still other embodiments atleast about 100. In some embodiments the lenses have tensile moduli lessthan about 100 psi.

It will be appreciated that all of the tests specified herein have acertain amount of inherent test error. Accordingly, results reportedherein are not to be taken as absolute numbers, but numerical rangesbased upon the precision of the particular test.

Modulus (tensile modulus) is measured by using the crosshead of aconstant rate of movement type tensile testing machine equipped with aload cell that is lowered to the initial gauge height. A suitabletesting machine includes an Instron model 1122. A dog-bone shaped samplefrom a −1.00 power lens having a 0.522 inch length, 0.276 inch “ear”width and 0.213 inch “neck” width is loaded into the grips and elongatedat a constant rate of strain of 2 in/min. until it breaks. The initialgauge length of the sample (Lo) and sample length at break (Lf) aremeasured. At least five specimens of each composition are measured andthe average is reported. Tensile modulus is measured at the initiallinear portion of the stress/strain curve.Percent elongation is=[(Lf−Lo)/Lo]×100.

Diameter may be measured using the modulation image generated from aMach-Zehnder interferometer with the lenses submersed in saline solutionand mounted concave surface down in a cuvette, as further described inUS2008/0151236. The lenses are equilibrated for 15 minutes at about 20°C. before measurement.

Water content is measured as follows. The lenses to be tested areallowed to sit in packing solution for 24 hours. Each of three test lensare removed from packing solution using a sponge tipped swab and placedon blotting wipes which have been dampened with packing solution. Bothsides of the lens are contacted with the wipe. Using tweezers, the testlens are placed in a weighing pan and weighed. The two more sets ofsamples are prepared and weighed as above. The pan and lenses areweighed three times and the average is the wet weight.

The dry weight is measured by placing the sample pans in a vacuum ovenwhich has been preheated to 60° C. for 30 minutes. Vacuum is applieduntil at least 0.4 inches Hg is attained. The vacuum valve and pump areturned off and the lenses are dried for four hours. The purge valve isopened and the oven is allowed reach atmospheric pressure. The pans areremoved and weighed. The water content is calculated as follows:

Wet  weight = combined  wet  weight  of  pan  and  lenses − weight  of  weighing  panDry  weight = combined  dry  weight  of  pan  and  lens − weight  of  weighing  pan$\mspace{20mu}{{\%\mspace{14mu}{water}\mspace{14mu}{content}} = {\frac{\left( {{{wet}\mspace{14mu}{weight}} - {{dry}\mspace{14mu}{weight}}} \right)}{{wet}\mspace{14mu}{weight}} \times 100}}$

The average and standard deviation of the water content are calculatedfor the samples are reported.

Lysozyme and lipocalin uptake were measured out using the followingsolutions and method.

The lysozyme solution contained lysozyme from chicken egg white (Sigma,L7651) solubilized at a concentration of 2 mg/ml in phosphate salinebuffer supplemented by Sodium bicarbonate at 1.37 g/l and D-Glucose at0.1 g/l.

The lipocalin solution contained B Lactoglobulin (Lipocalin) from bovinemilk (Sigma, L3908) solubilized at a concentration of 2 mg/ml inphosphate saline buffer supplemented by Sodium bicarbonate at 1.37 g/land D-Glucose at 0.1 g/l.

Three lenses for each example were tested using each protein solution,and three were tested using PBS as a control solution. The test lenseswere blotted on sterile gauze to remove packing solution and asepticallytransferred, using sterile forceps, into sterile, 24 well cell cultureplates (one lens per well) each well containing 2 ml of lysozymesolution. Each lens was fully immersed in the solution. 2 ml of thelysozyme solution was placed in a well without a contact lens as acontrol.

The plates containing the lenses and the control plates containing onlyprotein solution and the lenses in the PBS, were parafilmed to preventevaporation and dehydration, placed onto an orbital shaker and incubatedat 35° C., with agitation at 100 rpm for 72 hours. After the 72 hourincubation period the lenses were rinsed 3 to 5 times by dipping lensesinto three (3) separate vials containing approximately 200 ml volume ofPBS. The lenses were blotted on a paper towel to remove excess PBSsolution and transferred into sterile conical tubes (1 lens per tube),each tube containing a volume of PBS determined based upon an estimateof lysozyme uptake expected based upon on each lens composition. Thelysozyme concentration in each tube to be tested needs to be within thealbumin standards range as described by the manufacturer (0.05 micogramto 30 micrograms). Samples known to uptake a level of lysozyme lowerthan 100 μg per lens were diluted 5 times. Samples known to uptakelevels of lysozyme higher than 500 μg per lens (such as etafilcon Alenses) are diluted 20 times.

1 ml aliquot of PBS was used for samples 9, CE2 and the balafilconlenses, and 20 ml for etafilcon A lens. Each control lens wasidentically processed, except that the well plates contained PBS insteadof either lysozyme or lipocalin solution.

Lysozyme and Lipocalin uptake was determined using on-lens bicinchoninicacid method using QP-BCA kit (Sigma, QP-BCA) following the proceduredescribed by the manufacturer (the standards prep is described in thekit) and is calculated by subtracting the optical density measured onPBS soaked lenses (background) from the optical density determined onlenses soaked in lysozyme solution.

Optical density was measured using a SynergyII Micro-plate readercapable for reading optical density at 562 nm.

Lysozyme activity was measured using the solution and incubationprocedure described above for lysozyme uptake.

After the incubation period the lenses were rinsed 3 to 5 times bydipping lenses into three (3) separate vials containing approximately200 ml volume of PBS. The lenses were blotted on a paper towel to removeexcess PBS solution and transferred into sterile, 24 well cell cultureplates (one lens per well) each containing 2 ml of extraction solutioncomposed of a 50:50 mix of 0.2% of trifluoroacetic acid and acetonitrile(TFA/ACN) solution. The lenses were incubated in the extraction solutionfor 16 hours at room temperature.

In parallel, the lysozyme control solution was diluted in the extractionbuffer to a range of concentrations with bracket the expected lysozymeuptake of the lenses being analyzed. For the examples of the presentapplication the expected lysozyme concentrations were 10, 50, 100, 800and the control solution were diluted to those concentrations andincubated for 16 hours at room temperature. The lysozyme extracts fromboth the lenses and the controls were assayed for lysozyme activityusing EnzChek® Lysozyme Assay Kit (invitrogen) following theinstructions described by the manufacturer.

The EnzChek kit is a fluorescence based assay to measure levels oflysozyme activity in solution down to 20 U/ml. The test measureslysozyme activity on Micrococcus Lysodeikticus cell walls, which arelabelled in such a degree that the fluorescence is quenched. Lysozymeaction relieves this quenching, yielding an increase in fluorescencethat is proportional to lysozyme activity. The fluorescence increase ismeasured using a fluorescence microplate reader that can detectfluorescein using excitation/emission weivelenghs of 494/518 nm. ASynergy HT microplate reader was used in the examples of the presentapplication.

The assay is based on the preparation of lysozyme standard curve usingthe same lysozyme incubated with the lenses or as a control. Lysozymeactivity is expressed in fluorescence units and plotted against lysozymeconcentrations expressed in Units/ml. Activity of lysozyme extractedfrom the lenses as well as lysozyme control was measured and convertedusing standard curve to an activity expressed in units per ml.

The percentage of active or native lysozyme is determined by comparinglysozyme activity on lenses to that in the control solution and iscalculated following the formula below:

% of active or native lysozyme on lens=Lysozyme (unit/ml) extracted fromthe lens X100/Lysozyme (unit per ml) obtained from control.

PQ1 uptake was measured as follows. The HPLC is calibrated using aseries of standard PQ1 solutions prepared having the followingconcentrations: 2, 4, 6, 8, 12 and 15 μg/mL. Lenses were placed intopolypropylene contact lens case with 3 mL of Optifree Replenish (whichcontains 0.001 wt % PQ1, and is commercially available from Alcon). Acontrol lens case, containing 3 mL of solution, but no contact lens wasalso prepared. The lenses and control solutions were allowed to sit atroom temperature for 72 hours. 1 ml of solution was removed from each ofthe samples and controls and mixed with trifluoroacetic acid (10 μL).The analysis was conducted using HPLC/ELSD and a Phenomenex Luna C4 (4.6mm×5 mm; 5 μm particle size) column and the following conditions

Instrument: Agilent 1200 HPLC or equivalent with Sedere Sedex 85 ELSD

Sedex 85 ELSD: T=60° C., Gain=10, Pressure=3.4 bar, Filter=1 s

Mobile Phase A: H₂O (0.1% TFA)

Mobile Phase B: Acetonitrile (0.1% TFA)

Column Temperature: 40° C.

Injection Volume: 100 μL

TABLE I HPLC Conditions. Time Flow Rate (minutes) % A % B (mL/min) 0.00100 0 1.2 1.00 100 0 1.2 5.00 5 100 1.2 8.50 5 100 1.2 8.60 100 0 1.211.00 100 0 1.2

Three lenses were run for each analysis, and the results were averaged.

Oxygen permeability (Dk) was determined by the polarographic methodgenerally described in ISO 9913-1: 1996(E), but with the followingvariations. The measurement is conducted at an environment containing2.1% oxygen. This environment is created by equipping the test chamberwith nitrogen and air inputs set at the appropriate ratio, for example1800 ml/min of nitrogen and 200 ml/min of air. The t/Dk is calculatedusing the adjusted oxygen concentration. Borate buffered saline wasused. The dark current was measured by using a pure humidified nitrogenenvironment instead of applying MMA lenses. The lenses were not blottedbefore measuring. Four lenses were stacked instead of using lenses ofvaried thickness. A curved sensor was used in place of a flat sensor.The resulting Dk value is reported in barrers.

These examples do not limit the invention. They are meant only tosuggest a method of practicing the invention. Those knowledgeable incontact lenses as well as other specialties may find other methods ofpracticing the invention. However, those methods are deemed to be withinthe scope of this invention.

EXAMPLES

The following abbreviations are used in the examples below:

Macromer Macromer prepared according to the procedure disclosed underMacromer Preparation in Example 1, of US-2003-0052424-A1

acPDMS bis-3-acryloxy-2-hydroxypropyloxypropyl polydimethylsiloxane (MW2000, acrylated polydimethylsiloxane) from Degussa

Blue HEMA the reaction product of Reactive Blue 4 and HEMA, as describedin Example 4 of U.S. Pat. No. 5,944,853

CGI 819 bis(2,4,6-trimethylbenzoyl)-phenylphosphineoxide

CGI 1850 1:1 (wgt) blend of 1-hydroxycyclohexyl phenyl ketone andbis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentyl phosphine oxide

D3O 3,7-dimethyl-3-octanol

DMA N,N-dimethylacrylamide

EGDMA ethyleneglycol dimethacrylate

HEMA 2-hydroxyethyl methacrylate

MAA methacrylic acid

mPDMS monomethacryloxypropyl terminated mono-n-butyl terminatedpolydimethylsiloxane, manufactured by Gelest, molecular weight specifiedin the Examples

Norbloc 2-(2′-hydroxy-5-methacrylyloxyethylphenyl)-2H-benzotriazole

mPDMS-OH mono-(3-methacryloxy-2-hydroxypropyloxy)propyl terminated,mono-butyl terminated polydimethylsiloxane, made according to Example 8,molecular weight 612

PBS phosphate buffered saline, containing calcium and magnesium (Sigma,D8662).

PQ-1 Polyquaternium-1(dimethyl-bis[(E)-4-[tris(2-hydroxyethyl)azaniumyl] but-2-enyl]azaniumtrichloride)

PVP poly(N-vinyl pyrrolidone) (K values noted)

SiGMA(3-methacryloxy-2-hydroxypropyloxy)propylbis(trimethylsiloxy)silane

TEGDMA tetraethyleneglycol dimethacrylate

TPME tripropylene methyl ether

Examples 1-3

Lenses having the formulations shown in Table 1 were made as follows.The diluent for Examples 1-3 was a mixture of 18. 33 gm PVP 2500/48.34gm t-amyl alcohol. The diluent for Example 4 was 16.2 gm PVP 2500/64.8gm t-amyl alcohol. The monomer mixes were dispensed into Zeonor frontand Zeonor:Polypropylene (55:45) back curves. The monomer mixtures werecured under visible light (Philips TL-03 bulbs) in a nitrogen atmosphere(about 3% 0₂) using the following cure profile: 1 mW/cm² for about 20seconds at ambient temperature, 1.8±0.5 mW/cm² for about 270 seconds at75±5° C., and 6.0±0.5 mW/cm² for about 270 seconds at about 75±5° C.

After curing, the molds were opened, and the lenses released in 70% IPAin DI water. After about 40-50 minutes the lenses were transferred into:i) 70% IPA in DI water for about 40-50 minutes; ii) 70% IPA in DI waterfor about 40-50 minutes; and iii) DI water for at least about 30minutes.

The lenses were packaged in 950+/−50 uL of borate buffered sodiumsulfate solution with 50 ppm methyl cellulose (SSPS) using polypropylenebowls and foil, and autoclaved once (124° C., 18 minutes).

TABLE 1 Component Ex 1 Ex 2 Ex 3 Ex 4 CE 1 Macromer 0 0 0 6.93 0HO-mPDMS 1000 0 0 0 45.54 0 SiGMA 30 30 30 0 28  acPDMS 2000 5 5 5 0 0mPDMS 1000 28 28 28 0 31  DMA 19 19 19 19.8 24  HEMA 7.75 8.25 7.1512.41 6 MAA 1 0.5 1.6 1 0 Norbloc 2 2 2 2.18 2 PVP 360,000 7 7 7 11.88 7Blue HEMA 0.02 0.02 0.02 0.02   0.02 CGI 819 0.23 0.23 0.23 0.25   0.25* Sum of monomers 100 100 100 100 100  Diluent: 40 40 40 44.75 23** *CGI 1850 **D3O

Example 4

Lenses were made using the formulation listed in Table 1, for Example 4,and the conditions described in Example 1, except that the cure profilewas: 1 mW/cm² (10-30 seconds, ambient temperature), 1.5±0.2 mW/cm²(about 160 seconds, at 80±5° C.), 6.0±0.2 mW/cm² (about 320 seconds, atabout 80±5° C.)].

The molds were opened, and the lenses released in 70% IPA in DI water.After 60 minutes the lenses were transferred into: i) 100% IPA for 60minutes; ii) 70% IPA in DI water for 60 minutes; iii) DI water for 30minutes; iv) DI water for 30 minutes; v) DI water for 30 minutes.

The lenses were silver-treated by exposure to aqueous sodium iodidesolution, followed by exposure to aqueous silver nitrate solution. Thelenses were packaged in 10 mL of SSPS in glass vials with siliconestoppers, and autoclaved three times (121° C., 30 minutes).

Stability Evaluation

Lenses from Examples 1-4 and Comparative Example 1 were placed in achamber with temperature controlled at 55° C. Lenses were pulled fromthe chamber at established intervals, and tested for modulus, maximumstrain and diameter (for Examples 1-3, lenses were pulled at each timepoint for measurement as follows: 8-10 lenses for diameter measurement,9 lenses for % H₂O and 8-10 lenses for mechanical property testing; forExample 4, 5 lenses were pulled at each time point as follows: 5 lensesfor diameter testing, 9 lenses for % H₂O and 5 lenses for mechanicalproperties). The stability data from Examples 1-4 is shown in FIG. 1. Inaddition, stability data from lenses made according to ComparativeExample 1, below, which had no ionic component, are also included as anon-ionic control.

The modulus of the lenses was measured at various time intervals and isreported in Tables 2 and 3.

TABLE 2 Stability [MAA] Modulus Elongation Diameter Ex # Product wt %MAA Time (wk) (psi) (%) (mm) 1 0.0017 1 0.12 0 81 + 7 252 + 47 13.66 +0.06 1 0.0017 1 0.12 2 80 + 6 243 + 20 13.59 + 0.06 1 0.0017 1 0.12 588 + 6 163 + 28 13.59 + 0.14 1 0.0015 1 0.12 10 92 + 8 175 + 34 13.56 +0.05 1 0.0017 1 0.12 18 117 + 11 112 + 34 13.54 + 0.1  2 0.0008 0.5 0.060 81 + 8 294 + 42 13.53 + 0.04 2 0.0008 0.5 0.06 2 81 + 5 284 + 4113.59 + 0.05 2 0.0008 0.5 0.06 5 85 + 5 216 + 15 13.49 + 0.08 2 0.00080.5 0.06 10 NM NM NM 2 0.0008 0.5 0.06 18 118 + 8  144 + 20 13.49 + 0.123 0.0026 1.6 0.19 0 72 + 5 210 + 67 14.00 + 0.07 3 0.0026 1.6 0.19 281 + 6 169 + 37 13.94 + 0.05 3 0.0024 1.6 0.19 5 97 + 4 104 + 26 13.89 +0.04 3 0.0026 1.6 0.19 10 131 + 7   81 + 15 13.72 + 0.06 3 0.0026 1.60.19 18 174 + 11  48 + 11 13.62 + 0.07 * Moles/100 gram of reactivecomponents

TABLE 3 Stability [MAA] Modulus Elongation Diameter Ex # Product wt %MAA* Time (wk) (psi) (%) (mm) 4 0.00019 1 0.12 0 47 + 8   73 + 5113.89 + 0.04 4 0.00019 1 0.12 1 56 + 11 169 + 97 13.94 + 0.09 4 0.000191 0.12 4 59 + 15 106 + 56 13.92 + 0.05 4 0.00019 1 0.12 6 NM NM NM 40.00019 1 0.12 8 53 + 1  140 + 73 13.91 + 0.1  CE1 0 0 0 0 100 + 5 247 + 45 14.05 + 0.02 CE1 0 0 0 1 109 + 11  234 + 52 14.07 + 0.01 CE1 00 0 4 112 + 3  220 + 52 14.05 + 0.02 CE1 0 0 0 6 104 + 9  249 + 3814.08 + 0.02 CE1 0 0 0 8 106 + 16  202 + 61 14.05 + 0.01 *Moles/100 gramof reactive components

FIG. 1 is a graph showing of the modulus vs. time data included inTables 2 and 3, above. The lines for the comparative Example and Example4 are very flat, due to the small changes in modulus over the timeperiods measured. As the concentration of methacrylic acid and moleproduct increases, the slope of the line also increases, with asubstantial increase between Examplel (having a concentration of 1 wt %methacrylic acid and a stability product of 0.0017) and Example 3,having a concentration of 1.6 wt % methacrylic acid and a mole productof 0.0024. The changes in lens diameter and strain provide additionalconfirmation of trends observed in the modulus.

FIG. 1 clearly shows the relationship between hydrolytic stability oflenses, and the mole product of anionic group (carboxylate) and TMSsilicon content. Only moles of silicon (Si) derived fromtrimethylsilyl-containing monomers (TRIS or SIMAA2) were used in thecalculation of the mole product listed in Tables 2 and 3. From theseexperiments it was surprisingly found that the stability of siliconehydrogel lenses comprising a silicone component having at least one TMSgroup and at least one anionic component, such as methacrylic acid,display a sharp drop in stability above a certain concentration of theanionic component. Thus, Examples 1 and 2 have substantially similarstability even though the Example 1 contains twice as much methacrylicacid (1%) than Example 2 (0.5%). However, the stability of the lensesmade in Example 3 were much worse than Examples 2 and 3. This result wasunexpected, and provides a small formulating window for includinganionic components and silicone components comprising at least one TMSgroup. The inclusion of TMS containing silicone monomer components inamounts that provide the recited stability products provides the abilityto balance stability with other properties, such as a desired modulus,elongation or tan delta. The stability products, methacrylic acidconcentrations and % change in modulus are shown in Table 8, below.

Comparative Example 1

The reactive monomer mixture listed in Table 1 under CE 1 was dosed intoZeonor front curves, and the molds were closed using Zeonor back curves.The lenses were cured under visible light in a nitrogen atmosphere. Cureprofile: 1) Pre-cure (TLDK-30W/03 bulbs, 30-120 sec, 60-80° C.); 2) Cure(TLD-30W/03 bulbs, 320-800 sec, 70-80° C.). The molds were opened, andthe lenses released were extracted and hydrated in IPA/water mixtures.The finished lenses were packaged in borate buffered saline.

Example 5

A monomer mixture was formed by mixing the components in the amountslisted in Table 4. The monomer mixes were dispensed into Zeonor frontand Zeonor:Polypropylene (55:45) back curves. The molds were closed andthe filled, closed monomers were held at 65° C. with no irradiation. Themonomer mixtures were cured under visible light (Philips TL-03 bulbs) at65° C. in a nitrogen atmosphere (about 3% 0₂) using the following cureprofile: 1.5 mW/cm² for about 330 seconds, 7±01 mW/cm² for about 440seconds.

After curing, the molds were opened, and the lenses released in 70% IPAin DI water. After about 60-70 minutes the lenses were transferred into:i) 70% IPA in DI water for about 30-40 minutes; ii) 70% IPA in DI waterfor about 30-40 minutes; and iii) DI water for at least about 30minutes.

The lenses were packaged in 950+/−50 uL of borate buffered sodiumsulfate solution with 50 ppm methyl cellulose (SSPS) using polypropylenebowls and foil, and autoclaved once (124° C., 18 minutes).

TABLE 4 Component Wt % HO-mPDMS 1000 55 DMA 13.53 HEMA 12.5 TEGDMA 3 MAA1.5 Norbloc 2.2 PVP 360,000 12 Blue HEMA 0.02 CGI 819 0.25 Sum ofmonomers 100 Diluent (TPME): 45

The lenses were placed in a chamber with the temperature controlled at55° C. Lenses were pulled from the chamber at 5, 10 weeks, and testedfor modulus, maximum strain, diameter and % water. The results are shownin Table 5.

TABLE 5 Example 5, 100% TPME Properties Baseline 5 weeks 10 weeksModulus (psi)  93 ± 10 105 ± 8  102 ± 13 Elongation (%) 231 ± 61 206 ±43 196 ± 39 Gravimetric H₂O (%) 52.2 ± 0.2 52.2 ± 0.1 52.5 ± 0 

Examples 6 and 7

Example 5 was repeated, except that the diluent was changed to thoseshown in Tables 6-7 below. The lenses were placed in a chamber with thetemperature controlled at 55° C. Lenses were pulled from the chamber at5, 10, 15 and 20 weeks, and tested for modulus, maximum strain anddiameter, % water. The stability data from Examples 6-7 is shown inFIGS. 3 and 4.

TABLE 6 Example 6, 100% 3-methyl-3-pentanol Baseline 5 weeks 10 weeks 15weeks 20 weeks Modulus (psi) 98 85 86 87 94 Elongation (%) 179 182 174163 147 Gravimetric 53.1 54.6 53.5 53.9 54.0 H₂O (%) Diameter (mm) 12.6212.44 12.42 12.45 12.50 (−6.00 lens)

TABLE 7 Example 7, 75% butoxy ethyl acetate/35% 3-methyl-3-pentanolProperties Baseline 5 weeks 10 weeks 15 weeks 20 weeks Modulus (psi) 8483 71 75 83 Elongation (%) 232 184 209 169 178 Gravimetric 53.3 54.253.7 53.8 54.1 H₂O (%) Diameter (mm) 14.43 14.48 14.50 14.48 14.46(−1.00 lens)

The stability product, weight % methacrylic acid and percent change inmodulus for each of the Examples is shown in Table 8, below.

TABLE 8 Stability [MAA] Δ modulus Δ modulus Ex # Product (wt %) [MAA]* @10 wk (%) @ 18 wk (%) 1 0.0017 1 0.012 14 44 2 0.0008 0.5 0.006 NM 46 30.0026 1.6 0.019 35 141  4 0.00019 1 0.006  13* NM CE1 0 0 0  12* NM 5 01.5 0.017   9.7 NM 6 0 1.5 0.017 −12    −4** 7 0 1.5 0.017 −15    −1***measurements taken at 8 weeks **measurements taken at 20 weeks.

The modulus change noted for Comparative Example 1 illustrates thatmodulus can vary by as much as 10% without an anionic component. This isalso shown by the standard deviations noted in Tables 2 and 3. Thechange in modulus reported for Examples 6 and 7 are reported as negativevalues because the modulus was slightly lower after 10 and 20 weeks.However, the changes are within the standard deviation for the modulustest method, and should be considered as representing no change. Table 8also shows that the best results were achieved in formulations which didnot have any silicone monomers having TMS group(s) as a component in thereaction mixture (Example 4, which had mPDMS and macromer, and Examples5-7 which had HO-mPDMS). The Examples which had PDMS-type silicone asthe only silicone (Examples 5-7) displayed the best stability.

Example 8

To a stirred solution of 45.5 kg of 3-allyloxy-2-hydroxypropanemethacrylate (AHM) and 3.4 g of butylated hydroxy toluene (BHT) wasadded 10 ml of Pt (0) divinyltetramethyldisiloxane solution in xylenes(2.25% Pt concentration) followed by addition of 44.9 kg ofn-butylpolydimethylsilane. The reaction exotherm was controlled tomaintain reaction temperature of about 20° C. After complete consumptionof n-butylpolydimethylsilane, the Pt catalyst was deactivated byaddition of 6.9 g of diethylethylenediamine. The crude reaction mixturewas extracted several times with 181 kg of ethylene glycol untilresidual AHM content of the raffinate was <0.1%. 10 g of BHT was addedto the resulting raffinate, stirred until dissolution, followed byremoval of residual ethylene glycol affording 64.5 kg of the OH-mPDMS.6.45 g of 4-Methoxy phenol (MeHQ) was added to the resulting liquid,stirred, and filtered yielding 64.39 kg of final OH-mPDMS as colorlessoil.

Example 9 and Comparative Example 2

The components listed in Table 9, (except PVP K90) were mixed in a jarfor at least 1 hour with stirring. The PVP K90 was slowly added to thereactive mixture with stirring such that no clumps were formed duringthe addition. After all the PVP had been added the reactive mixture wasstirred for an additional 30 minutes. The jar was sealed and put on ajar roller running at ˜200 rpm over night.

The reactive mixture was degassed in a vacuum desiccator (around 1 cm Hgpressure) for about 40 minutes. The plastic lens molds and monomerdosing syringes were put in a N₂ environment (<2% O2) for at least 12hours. The back curve mold was made of 9544 polypropylene, and the frontcurve mold was made of Zeonor™. The reactive mixture (50 microliter) wasdosed into each FC curve, and then BC curve was slowly deposited toclose the molds. This process was carried out under N2 environment (<2%0₂).

The monomer mixtures were cured under visible light (Philips TLK 40 W/03bulbs) in a nitrogen atmosphere (about <2% 0₂) using the following cureprofile: 5±0.5 mW/cm² for about 10 minutes at about 50±5° C.

The base curve was the removed from the assembly by prying. The lensremained with the front curve and the front curve was press-inverted toseparate the dry lens from the front curve.

The dry lenses were inspected. Passed lenses were packaged in blisterwith 950 ul borate buffered packing solution with 50 ppm methyl ethylcellulose for each lens. The lens was then sterilized at 121° C. for 18minutes

TABLE 9 Wt % Component Ex. 9 CE 2 HO-mPDMS 55 55 TEGDMA 0.25 0.25 DMA16.78 18.28 HEMA 12.5 12.5 MAA 1.5 0 PVP K-90 12 12 CGI 819 0.25 0.25Norbloc 1.7 1.7 Blue HEMA 0.02 0.02Lysozyme and lipocalin uptake were measured as described above.

Lysozyme is a hydrolytic enzyme able to cleave the cell wall of grampositive and some gram negative bacteria. Cleavage of the peptidoglycanwall at the β1-4 linkage between N-acetyl-glucosamine and N acetylgalactosamine (muramate) results in lysis of the bacteria.

Lysozyme activity was measured to determine the capacity of lenses tomaintain this protein in its native state. The level of native lysozymecorresponds to the level of active lysozyme determined following theprocedure described above. The results are shown in Table 10.

TABLE 10 [ion] Lysozyme Lipocalin % Native PQ1 Ex. # wt % [ion]* (μg)(μg) lysozyme uptake 9 1.5 0.017 103 + 5  4.6 ± 0.4 60 ± 7.7 90 CE 2 0 06.6 ± 0.3 6.5 ± 0.6 30 ± 3   6 Balafilcon 1 0.006 46 ± 6  7.8 ± 0.5 37 ±8.3 6 A Etafilcon 1.98 0.023 843 ± 23  1.8 ± 0.2 80 ± 11  2 A *Moles/100gram of reactive components Balafilcon A is the lens material used tomake Purevision ® lenses commercially available from Bausch & LombEtafilcon A is the lens material used to make ACUVUE ® AND ACUVUE ®2lenses commercially available from Johnson & Johnson Vision Care, Inc.

Preservatives uptake from lens care solutions can impact contact lensperformance, particularly contact lens induced corneal stainingPreservative uptake of the lenses of Example 9, Comparative Example 2,and Purevision was measured by incubating the above lenses in 3 ml ofOptiFree® RepleniSH® for 72 hours at room temperature using theprocedure described above to lysozyme and lipocalin uptake. OptiFree®RepleniSH® contains 0.001 wt % PQ1 as a disinfectant/preservative andcitrate dihydrate and citric acid monohydrate concentrations are 0.56%and 0.021% (wt/wt). The quantity of PQ1 uptake was determined using HPLCanalysis by comparing the level of PQ1 in the initial soak solution tothe level of PQ1 after 72h soak in presence of the test contact lens.The results are shown in Table 10.

Examples 10-18 & Comparative Example 2

Formulations were made as in Example 9, but varying the concentration ofmethacrylic acid as shown in Table 11, below. The lysozyme and PQ1uptake were measured as in Example 9, and the results are shown in Table12, below. The results are also shown graphically in FIG. 1.

TABLE 9 Wt % Component CE 2 Ex 10 Ex 11 Ex 12 Ex 13 Ex 14 Ex 15 Ex 16 Ex17 Ex 18 HO- 55 55 55 55 55 55 55 55 55 55 mPDMS TEGDMA 0.25 0.25 0.250.25 0.25 0.25 0.25 0.25 0.25 0.25 DMA 18.28 18.08 17.88 17.68 17.4817.28 17.08 16.88 16.78 16.68 HEMA 12.5 12.5 12.5 12.5 12.5 12.5 12.512.5 12.5 12.5 MAA 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.5 1.6 PVP K-90 12 1212 12 12 12 12 12 12 12 CGI 819 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.250.25 0.25 Norbloc 1.7 1.7 1.7 1.7 1.7 1.7 1.7 1.7 1.7 1.7 Blue 0.02 0.020.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 HEMA

TABLE 10 PQ1 (%) Lysozyme Ex # MAA wt % [MAA] * per lens (mg/lens) CE2 00  0 (0)  6.78 (0.48) 10 0.2 0.002  0.0 14.23 (1.7)  11 0.4 0.004 2.05(2.0) 21.23 (2.31) 12 0.6 0.007 0.36 (0.5) 37.76 (3.51) 13 0.8 0.009 0.0 38.41 (2.93) 14 1 0.012 12.92 (4.4)   56.55 (10.39) 15 1.2 0.01442.7 16 1.4 0.016 51.5 17 1.5 0.017 84.5 (7.8)   83 (7.21) 18 1.6 0.01972.6 * Moles/100 gram of reactive components

As is seen in FIG. 5, formulations can be made which display desirablelysozyme uptake, and low PQ1 uptake with existing contact lens caresolutions. Thus ophthalmic devices of the present invention display abalance of desirable protein uptake, compatibility with existing lenscare solutions and thermal stability.

We claim:
 1. A polymer formed from reactive components comprising about0.2 to about 0.8 weight % of at least one anionic component and at leastone silicone component selected from the group consisting of reactivepolydialkylsiloxane selected from compounds of Formula I:

wherein b=2 to 20; one terminal R¹ comprises at least one ethylenicallyunsaturated moiety, the remaining terminal R¹ are independently selectedfrom the group consisting of monovalent alkyl groups having 2 to 16carbon atoms, and the remaining R¹ are selected from the groupconsisting of monovalent alkyl groups having 1 to 16 carbon atoms,wherein said polymer absorbs at least about 10 μg lysozyme and less thanabout 5 μg lipocalin.
 2. The polymer of claim 1 wherein said at leastone silicone component is selected from monomethacryloxypropylterminated mono-n-butyl terminated polydimethylsiloxane,bis-3-acryloxy-2-hydroxypropyloxypropyl polydialkylsiloxane, andmono-(3-methacryloxy-2-hydroxypropyloxy)propyl terminated, mono-butylterminated polydialkylsiloxane combinations thereof and the like.
 3. Thepolymer of claim 1 wherein said anionic component is a carboxylic acidcontaining component selected from the group consisting of free radicalreactive carboxylic acids comprising 1-8 carbon atoms.
 4. The polymer ofclaim 3 wherein said carboxylic acid-containing component is selectedfrom the group consisting of (meth)acrylic acid, acrylic acid, itaconicacid, crotonic acid, cinnamic acid, vinylbenzoic acid, fumaric acid,maleic acid, N-vinyloxycarbonyl alanine and mixtures thereof.
 5. Thepolymer of claim 3 wherein said carboxylic acid-containing componentcomprises methacrylic acid.
 6. The polymer of claim 1 wherein at leastabout 50% of all proteins absorbed in or on said polymer are in nativeform.
 7. The polymer of claim 1 wherein said anionic component comprisesat least one polymerizable group and three to ten carbon atoms.
 8. Thepolymer of claim 1 wherein said anionic component comprises three toeight carbon atoms.
 9. The polymer of claim 1 wherein said anioniccomponent comprises at least one carboxylic acid group.
 10. The polymerof claim 1 wherein said anionic component is selected from the groupconsisting of acrylic acid, methacrylic acid, furmaric acid, maelicacid, itaconic acid, crotonic acid, cinnamic acid, vinylbenzoic acid,monoesters of furmaric acid, maelic acid and itaconic acid andN-vinyloxycarbonyl alanine (N-vinyloxycarbonyl-β-alanine) andhomopolymers and copolymers thereof.
 11. The polymer of claim 1 whereinsaid polymer absorbs at least about 50 μg lysozyme.
 12. The polymer ofclaim 1 wherein said polymer absorbs at least about 100 μg lysozyme. 13.The polymer of claim 1 wherein said polymer absorbs at least about 200μg lysozyme.
 14. The polymer of claim 1 wherein said polymer absorbs atleast about 500 μg lysozyme.
 15. The polymer of claim 1 wherein saidpolymer absorbs at least about 800 μg lysozyme.
 16. The polymer of claim1 wherein said polymer absorbs about 3 μg or less lipocalin.
 17. Thepolymer of claim 1 wherein at least about 60% of all proteins absorbedin or on said polymer are in native form.
 18. The polymer of claim 1wherein at least about 75% of all proteins absorbed in or on saidpolymer are in native form.
 19. The polymer of claim 1 furthercomprising a water content of at least about 15%.
 20. The polymer ofclaim 1 further comprising a Dk of at least about
 50. 21. The polymer ofclaim 1 further comprising a contact angle of less than about 90°.